Credentials: MD, MS
Position title: Associate Professor
Phone: (608) 265-2319
600 Highland Ave Rm H4/638
Madison, WI 53792
MD University of Minnesota, Minneapolis, MN
MS University of Wisconsin, Madison, WI
My primary research interests focus on the prevention of ovarian cancer in a high-risk population by altering cellular energy metabolism.
The production, transformation and utilization of energy in a living organism is essential for biological activities. Emergences of aberrant metabolic characteristics can result survival and fitness of neoplastic cells. The anomalous characteristic of energy metabolism pathways in cancer cells has been the subject of extensive research. In the 1920s, the metabolic distinction between normal and tumor cells was reported by Otto Warburg, and subsequently termed ‘the Warburg effect’. The Warburg effect stipulates that even in the presence of sufficient oxygen, the malignant cells prefer to produce adenosine triphosphate (ATP) via glycolysis instead of oxidative phosphorylation.
Oxidative phosphorylation (OXPHOS) is a mechanism of producing energy that cancer cells are unusually good at exploiting. Cancer cells can shift between aerobic and anaerobic metabolism very easily. Blocking OXPHOS is one proven method to decrease cancer’s ability to recur, metastasize and become resistant to therapy, and is being studied in my laboratory.
We have identified small molecule inhibitors that share structural similarity with ubiquinone, a key player in energy metabolism and electron transport. YM-155, plumbagin and atovaquone are all examples of drugs that block oxidative phosphorylation. Atovaquone is the compound of greatest interest in our laboratory. It is an orally available medication that is already FDA-approved for the treatment of malaria—the ideal drug candidate for cancer prevention studies.
We have completed mechanistic and cancer growth experiments related to atovaquone, confirming its mechanism of action and anti-tumor activity. Current funding is focused on 1) testing atovaqoune’s ability to prevent ovarian cancer in a mouse model 2) studying potential mechanisms of resistance to atovaquone and 3) completing a window-of-opportunity clinical trial to confirm biologic plausibility.
New data from our laboratory suggests a synergistic effect between immune modulation (such as checkpoint inhibition) and OXPHOS inhibition. Tumors with low immunogenicity and thus low T cell infiltration are referred to as “cold” tumors. There is a building body of evidence that these “cold” tumors can be activated to induce immune responses, or made “hot,” by different approaches. One of these approaches is radiation therapy, which has been studied as stand-alone or in combination with checkpoint inhibitors. Cellular damage induced by irradiation has been observed to expose neoantigens that provoke T cell anti-tumor responses. Our lab provides an alternative approach through oxidative phosphorylation (OXPHOS) inhibitors. OXPHOS inhibitors are known to cause intracellular oxidative stress, leading to DNA and protein damage, and ultimately cell death. We hypothesize that treating ovarian cancer cell lines with OXPHOS inhibitors, particularly atovaquone, will produce alterations in their expressed proteome that may render them more immunogenic, and thus more susceptible to immunotherapies. This proposed project could be an opportunity for a motivated graduate student to take our lab’s research in an entirely new direction.